Thiazolopyrimidines

ABSTRACT

Substituted thiazolopyrimidines, e.g., 3-p-chlorophenyl-6,7dihydro-5H-thiazolo(3,2-a)pyrimidine hydrochloride, are prepared from phenacyl halides and propylene thiourea and are useful as CNS stimulants and analgesics.

United States Patent Manning June 20, 1972 541 Tl-IIAZOLOPYRIMIDINES[56] References Cited [72] Inventor: RObGll E- Manning, Mountain Lakes,NJ. OTHER PUBLICATIONS [73] Assignee: Sandoz-Wander, Inc., Hanover, NJ.0 A 71 81 401x 1969) [22] Filed: May 25, 1970 Chadha et 211., Can. J.Chem. 1969, 47(15), 2843- 4.

[211 Appl' 40367 Primary Examiner-Henry R. Jiles Rehed s Application mAssistant Examiner-R. V. Rush I Attorney-Gerald D. Sharkin, Frederick H.Weinfeldt, Robert [631 827,996 May 5. Honor, Walter F. Jewell andRichard E. Vila 1969, abandoned, which is a continuation-impart of Ser.No. 741,856, July 2, l968, abandoned, which is a A Tcontinuation-in-part of Ser. No. 680,307, Nov. 3, [57] ABSTR C 1967,abandoned. Substituted thiazolopyrimidines, e.g., 3-p-chlorophenyl-6,7-v dihydro-5H-thiazolo[3,2-a]pyrimidine hydrochloride, are [52] US. Cl...260/25l A, 260/25] R, 424/251 r d from henacyl halides and propylenethiourea and [5 l 1 Int. Clare useful as timulants and analgesics [58]Field of Search ..260/25 l A, 69 E 18 Claims, No DrawingsTHIAZOLOPYRIMIDINES This application is a continuation-in-part ofapplication Ser. No. 827,996, filed May 26, i969, now abandoned which inturn is a continuation-in-part of application Ser. No. 741,856, filedJuly 2,1968, now abandoned, which in turn is a continuation-in-part ofapplication Ser. No. 680,307, filed Nov. 3, 1967, now abandoned.

This invention relates to novel heterocyclic compounds. Moreparticularly, this invention pertains to novel 3-phenyl andB-substituted phenyl 6,7-dihydro-5H-thiazolo[3,2- a]pyrimidines and toacid addition salts thereof. This invention also pertains to methods forpreparing these compounds, to intermediates therefor, and to methods forthe preparation of the intermediates.

The thiazolopyrimidines of the present invention may be represented bythe following structural formula where R, R,, X andtheproviso are as setout above.

The pyrimidines of formula) are prepared from 'the compounds of formula(ll) or an acid addition salt thereof by treatment with a strongmineralacid at a temperature from about room temperature to about 100 C,preferably about 50 to 70 C. The mineral acid may be in dilute orconcentrated form and such acids as hydrochloric acid, sulfuric acid,phosphoric acid and the like may be utilized. The :reaction may beperformed in solvent but use of solvent and the particular solventutilized'is not considered critica'l. As illustrative of the solventswhich may be used there may be mentioned lower alkanols such as ethanol,isopropanol and the like, acetone, tetrahydrofuran,and similar inertsolvents.

The compounds of formula (II) in acid addition salt form (lla) may beprepared in accordance with the following reaction scheme:

o H H II 1 R1 -(l: x, s=

N 1% R E II) (IV) where R, R,, X and the proviso are as set out aboveand X represents bromine or chlorine.

Accordingly, the compounds of formula (lla) above are prepared bytreating a phenacyl halide (Ill), such as the bromide or chloride, e.g.,p-chloro phenacyl bromide, with propylenethiourea (IV) in solvent at atemperature of about 0 to 60 C. Preferred temperatures are about 10 to35 C. The solvents which may be used include acetone, lower alkanolssuch as ethanol, tetrahydrofuran and the like, although the particularsolvent used and the temperature are not critical.

As indicated above, the compounds of formulas (l) and (ll) above may berecovered as their acid addition salts. When it is desired to convertsuch salts to the corresponding free bases, conventional techniques maybe utilized, e.g., dissolution of the salt in water and precipitationusing a base such as sodium hydroxide.

The compounds of formula (II) may also be illustrated bytheir-tautomeric equivalents such as represented by the followingstructural formula where R, R,, X and the proviso are as set out above.

In order to simplify this description, however, formula (ll) only willbe used. it should be nevertheless undecstood that the compounds offormula (V) may be represented as well as thecompounds of formula-(ll)and both tautomeric fonns are within the concept of the presentinvention.

Certain of the phenacyl halides (1]!) above are known and are preparedby methods disclosed in the literature. Those not specifically disclosedare preparedfrom known materials in an analogousmanner.

The compounds of formulas (l) and (ll) are useful because they possesspharmacological activity in animals. More particularly, compounds (1)and (ll) with the exception of the compounds in which both R and X arehydrogen are useful as CNS stimulants and especially asanti-depressants, as indicated by their activity in mice testedaccording to the 30- word adjective check sheet system basicallydescribed by S. lrwin (Gordon Research Conference, Medicinal Chemistry,1959) and Chen (Symposium on Sedative and Hypnotic Drugs, Williams andWilkins, l954).

The compounds of formulas (l) and (ll) are also useful as analgesics asindicated by their activity in mice tested essentially by the WrithingMethod" of Seigmund et al. (Proc. Soc. Exp. Biol., 729, 1957) asmodified by Okun et al. (J. Pharmacol. & Exper. Therap., 139: 107,1963).

Furthermore, the compounds of formulas (l) and (II) may be similarlyadministered in the form of their non-toxic pharmaceutically acceptableacid addition salts. Such salts possess the same order of activity asthe free base, are readily prepared by reacting the base with anappropriate acid and accordingly are included within the scope of theinvention. Representative of such salts are the mineral acid salts, suchas the hydrochloride, hydrobromide, sulfate, phosphate and the like andthe organic acid salts, such as the succinate, benzoate, acetate,p-toluenesulfonate, benzene-sulfonate and the like.

When utilized for either of the above uses, the thiazolopyrimidines maybe combined with a pharmaceutically acceptable carrier or adjuvant andadministered orally or parenterally. For these uses, the dosage willvary depending upon the mode of administration utilized and theparticular compound employed. However, in general, satisfactory resultsare obtained for both the anti-depressant use and the analgesic use whenthe compounds are administered at a daily dosage of from about 0.5milligrams to 50 milligrams per kilogram of animal body weight. Thisdaily dosage is preferably given in divided doses, e.g., 2 to 4 times aday, or in sustained release form. For most large mammals, the totaldaily dosage is from about 15 to 300 milligrams, and dosage formssuitable for internal administration comprise from about 4 milligrams toabout 150 milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques which contains thefollowing:

EXAMPLE l 3-p-chlorophenyl-6,7-dihydro-S H-thiazolo[ 3 ,2-a]pyrimidinehydrochloride Step 1. 3-p-chlorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[ 3,2-alpyrimidine hydrobromide A solution of p-chlorophenacylbromide (12 g) in 70 ml acetone is added with stirring in one portion toa solution of propylenethiourea (6 g) in acetone (400 ml) at roomtemperature. After stirring for 1 and 3/4 hours, 16.4 g of the resultantproduct, 3p-chlorophenyl-3-hydroxy-2,3,6,7-tetrahydro-H-thiazolo[3,2-a1pyrimidine hydrobromide is collected byfiltration; m.p. 210 C.

The free base is prepared by suspending the salt in water, adding sodiumcarbonate, and collecting the resulting solid. Step 2.3-p-chlorophenyl-6,7-dihydro-5H-thiazolo[3,2- alpyrimidine hydrochlorideA mixture of 3-p-chlorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine, methanol (200 ml) andconcentrated HCl (40 ml) is refluxed for 3 hours and then evaporated invacuo. The resultant syrup is crystallized from ether to give 18g ofsolid which is then crystallized from methanol-ether (1:3) to give 12.2g of 3-p-chlorophenyl-6,7- dihydro-5H-thiazolo[3,2-a1pyrimidinehydrochloride; m.p. 269 to 271C.

EXAMPLE 2 3-phenyl-6,7-dihydro-5l-l-thiazolo[3,2-a1pyrimidinehydrochloride Step 1. 3-phenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazo1o[ 3 ,2-alpyrimidine hydrobromide A solution of phenacyl bromide(20 g) in acetone 150 ml) is added in one portion with stirring to asolution of propylenethiourea 1 1.2 g) in acetone 800 ml). Afterstirring for 1% hours, 30.5 g of the resultant product, 3-phenyl-3-hydroxy-2,3,6,7-tetrahydro-5 H-thiazolo[ 3 ,2-a]pyrimidine hydrobromideis collected by filtration; m.p. 197 C. Step 2.3-pheny1-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrochloride Amixture of 18 g of 3-phenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine (18 g) methanol (200 ml) andconcentrated l-lCl (40 ml) is refluxed for 3 hours. The resultantsolution is evaporated in vacuo. The resultant syrup is crystallizedfrom acetone to provide 1 1.8 g of 3-pheny1-6,7-dihydro-5H-thiazolol 3,2-a]pyrimidine hydrochloride; m.p. 222 to 224 C.

EXAMPLE 3 2,3-diphenyl6,7-dihydro-5H-tiazolo[ 3 ,2-a]pyrimidinehydrochloride A solution of desylchloride (23 g) in acetone (150 m1) isadded in one portion with stirring to a solution of propylenethiourea 11.6 g) in acetone (800 ml). After stirring for 2% hours, the resultantsolid is collected by filtration to give 27.0 g of2,3-diphenyl-3-hydroxy-2,3,6,7-tetrahydro-5l-lthiazolo[3,2-a]pyrimidinehydrochloride; m.p. 283 C.

Step 2. 2,3-diphenyl-6,7-dihydro-5H-thiazolo[ 3 ,2- alpyrimidinehydrochloride A mixture of 2,3-diphenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine hydrochloride 12 g), methanol ml) andconcentrated HCl (24 ml) is refluxed for 2 hours. The solution isevaporated in vacuo and the resultant syrup crystallized from acetone togive 2,3-dipheny1-6,7 dihydro-5H-thiazolo[3,2-a1pyrimidinehydrochloride; 9.2 g, m.p. 293 C.

EXAMPLE 4 3-p-methoxyphenyl-6,7-dihydro-5H-thiazolo[ 3 ,2-a ]pyrimidinehydrochloride l OCH:

Step I. 3-hydroxy-3-p-methoxyphenyl-2,3,6,7-tetrahydro-5H- thiazolo[3,2-alpyrimidine hydrobromide A solution of p-methoxyphenacyl bromide (l1.6 g) in acetone (80 ml) is added with stirring at room temperature toa solution of propylenethiourea (5.8 g) in acetone (500 ml). Afterstirring for l 'hours, the resultant solid is collected by filtration togive 3-hydroxy-3-methoxyphenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine hydrobromide (l3 );'m.p. 203 to205 C. Step 2. 3-p-methoxyphenyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrochloride A mixture of3-hydroxy-3-p-methoxyphenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine (5 g), methanol (200 ml) andconcentrated HCl (40 ml) is heated under reflux for 3 hours. Theresultant reaction mixture is evaporated in vacuo and the residue iscrystallized from acetone to give the crude product which is thenrecrystallized from methanolether (1:3) to afford 3.8 g of substantiallypure 3-p-methoxyphenyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidinehydrochloride; m.p. 257 to 258 C.

EXAMPLE 5 3-p-fluorophenyl-6,7-dihydro-5H-thiazolo[3,2-a1pyrimidinehydrochloride Step 1.3-p-fluorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5l-lthiazolo[3,2-a]pyrimidine hydrobromide A solution of p-fluorophenacyl bromide (11g) in acetone (80 ml) is added with stirring at room temperature to asolution of propylenethiourea (5.8 g) in acetone (500 ml). Afterstirring for 1% hours, the resultant solid is collected by filtration togive 14.9 g of 3-p-fluorophenyl 3-hydroxy-2,3,6,7-tetrahydro-H-thiazolo[3,2-a]pyrimidine hydrobromide; m.p. 294 to 296 C.Step 2. 3-p-fl uorophenyl-6,7-dihydro-5 H-thiaz0lo[ 3 ,2- a]pyrimidinehydrochloride A mixture of 3-p-fluorophenyl-3-hydroxy-2,3,6,7-tetrahydro-S H-thiazolo[3,2-a1pyrimidine (5 g), methanol (200 ml) andconcentrated HCl (40 ml) is heated under reflux for 16 hours. Theresultant reaction mixture is evaporated in vacuo and the residue iscrystallized from ether to give crude product. This product isrecrystallized from methanol-ether 1:3) to give3-p-fluorophenyl-6,7-dihydro-5H-thiazolo[3,2- a]pyrimidinehydrochloride; m.p. 242243 C. (with decom position).

EXAMPLE 6 3-p-biphenylyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine Step1; 3-p-biphenylyl-3-hydroxy-2,3,6,7-tetrahydro-5H- thiazolo[ 3,2-a1pyrimidine hydrobromide A solution of p-phenyl phenacyl bromide(6.9 g) in acetone (50 ml) is added with stirring at room temperature toa solution of propylenethiourea (2.9 g) in acetone (200 ml). Afterstirring for 5 hours, the resultant solid is collected by filtration togive 9.4 g of 3-p-biphenylyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine hydrobromide; mp 338 339 C withdecomposition. Step 2. 3-p-biphenyly]-6,7-dihydro-5H-thiazolo[ 3 ,2-a]pyrimidine hydrochloride A mixture of3-p-biphenylyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine (4.0 g), methanol (200 ml) and concentratedhydrochloric acid (40 ml) is heated under reflux for 24 hours. Theresulting reaction mixture is evaporated in vacuo and the residue iscrystallized from ether to give crude product which is recrystallizedfrom methanol-ether (1:3) to give 3-p-biphenylyl-6,7-dihydro-5H-thiazolo[ 3 .2-a] pyrimidine hydrochloride; m.p. 299-300 C withdecomposition.

EXAMPLE 7 3-a,a,a-trifluoro-m-tolyl-6,7-dihydro-5 H-thiazolo[ 3 .2-alpyrimidine hydrochloride Step 1.3-hydroxy-3-a,a,a-trifluoro-m-tolyl-2,3,6,7- tetrahydro-5H-thiazolo[3,2-a]pyrimidine hydrobromide A solution of m-trifluoromethyl phenacylbromide (7. l g) in acetone 50 ml) is added with stirring at roomtemperature to a solution of propylenethiourea 3.0 g) in acetone (200ml). After stirring for 2 hours, the resultant solid is collected byfiltration to give 9.4 g. of 3-hydroxy-3-a,a,a-trifluoro-m-tolyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine hydrobromide; m.p. l9l-l 92 C with decomposition. Step 2.3-a,a,a-trifluoro-m-tolyl-6,7-dihydro-5H-thiazolo [3,2-alpyrimidinehydrochloride A mixture of 3-hydroxy-3-a,a,a-trifluoro-m-tolyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine (5.0 g), methanol ml) andconcentrated hydrochloric acid 30 ml) is heated under reflux for 24hours. The resulting reaction mixture is evaporated in vacuo and theresidue is crystallized from acetone to give crude product which isrecrystallized from methanol-ether (1:3) to give3-a,oz,a-triflu0r0-m-t0lyl-6,7- dihydro-5H-thiazolo[3,2-a1pyrimidinehydrochloride; m.p. 208209 C with decomposition.

EXAMPLE 8 3-(3,4-dichlorophenyl)-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrochloride Step 1.3-(3,4-dichlorophenyl)-3-hydroxy-2,3,6,7-tetrahydro- H-thiazolo[3,2-a]pyrimidine hydrobromide A solution of 3,4-dichlorophenacyl bromide(13.3 g) in acetone 80 ml) is added with stirring at room temperature toa solution of propyle'nethiourea 5.8 g) in acetone (500 ml). Afterstirring for 1% hours, the resulting solid is collected by filtration togive 3-(3,4-dichlorophenyl)-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazo1o[3,2-a]pyrimidine hydrobromide. This compoundmelts at 200 C and resolidifies thereafter remelting at 260-270 C.

This intermediate product is converted to the free base form by additionto water, treating with sodium carbonate and collecting the resultingsolid.

Step 2. 3-(3,4-dichlorophenyl)-6,7-dihydro-5H-thiazolo[3,2-a ]pyrimidinehydrochloride A- mixture of 3-(3,4-dichlorophenyl)-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine (7.5 g), methanol 200 ml) andconcentrated hydrochloric acid 40 ml) is heated under reflux for 3hours. The resultant reaction mixture is evaporated in vacuo and theresidue is crystallized'from ether to give crude product. This productis recrystallized from methanol-ether (1:4) to give3-(3,4-dichlorophenyl)-6,7- dihydro-SH-thiazolol3,2-a]pyrimidinehydrochloride; m.p. 268270 C (with decomposition).

The corresponding free base is prepared by adding the salt to water,treating with sodium carbonate and collecting the resultingsolid. I

What is claimed is:

1. A compound of the formula 2. The compound of claim 1 which is3-p'chlorophenyl-6,7-

dihydro-S l-l-thiazolo[ 3,2-alpyrimidine.

3. The compound of claim 1 which is 3-phenyl-6,7-dihydro-5H-thiazolo[3,2-a1pyrimidine.

4. The compound of claim 1 which is 2,3-dipheny|-6,7- dihydro-SH-thiazolo[ 3,2-a1pyrimidine.

5. The compound of claim 1 which is3-(3,4-dichlorophenyl)-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine.

6. The compound of claim 1 which is 3-p-methoxyphenyl- 6,7-dihydro-5H-thiazolo[ 3 ,2-a]pyrimidine.

7. The compound of claim I which is 3-p-fluorophenyl-6,7-dihydro-5H-thiazolo[3,2-a1pyrimidine.

8. The compound of claim 1 which is 3-p-biphenylyl-6,7-dihydro-5H-thiazolo[ 3,2-a ]pyrimidine.

9. The compound of claim 1 which is 3-a,a, a-trifluoro-mtoll-6,7-dihydro-5H-thiazolo[3 2-a]pyrimidine.

0. A compound of the formu a 1 NO I it. i

where R is hydrogen or phenyl;

R, is hydrogen, chloro, fluoro, phenyl or lower alkoxy; and

X is hydrogen, trifluoromethyl or halo, provided that when X is chloro,R, is chloro, and when X is trifluoromethyl, R, is H, or an acidaddition salt thereof.

11. The compound ofclaim 10 which is 3-p-chlorophenyl-3-hydroxy-2,3,6,7-tetrahydr05H-thiaz0lo[ 3,2-a]pyrimidine.

12. The compound of claim 10 which is 3-phenyl-3-hydroxy-2,3,6,7-tetrahydro-5 H-thiazolo[ 3 ,2-alpyrimidine.

13. The compound of claim 10 which is 2,3-diphenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine.

14. The compound of claim 10 which is 3-(3,4-dichlorophenyl)-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrirnidine.

15. The compound of claim 10 which is3-hydroxy-3-pmethoxyphenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine.

16. The compound of claim 10 which is 3-p-fluorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine.

17. The compound of claim 10 which is 3-p-biphenylyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a1pyrimidine.

18. The compound of claim 10 which is 3-hydroxy-3-a,a,atrifluoro-m-tolyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a] pyrimidine.

* t k II! I

2. The compound of claim 1 which is3-p-chlorophenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 3. Thecompound of claim 1 which is3-phenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 4. The compound ofclaim 1 which is 2,3-diphenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.5. The compound of claim 1 which is3-(3,4-dichlorophenyl)-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 6. Thecompound of claim 1 which is3-p-methoxyphenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 7. Thecompound of claim 1 which is3-p-fluorophenyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 8. Thecompound of claim 1 which is3-p-biphenylyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 9. The compoundof claim 1 which is 3- Alpha , Alpha , Alpha-trifluoro-m-tolyl-6,7-dihydro-5H-thiazolo(3,2-a)pyrimidine.
 10. Acompound of the formula
 11. The compound of claim 10 which is3-p-chlorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.12. The compound of claim 10 which is 3-phenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.
 13. The compound of claim 10which is 2,3-diphenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.
 14. The compound of claim10 which is3-(3,4-dichlorophenyl)-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.
 15. The compound of claim 10 which is3-hydroxy-3-p-methoxyphenyl-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.16. The compound of claim 10 which is3-p-fluorophenyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.17. The compound of claim 10 which is3-p-biphenylyl-3-hydroxy-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.18. The compound of claim 10 which is 3-hydroxy-3- Alpha , Alpha , Alpha-trifluoro-m-tolyl-2,3,6,7-tetrahydro-5H-thiazolo(3,2-a)pyrimidine.